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HSPA13, an important member of the heat shock protein family, plays an essential role in the oncogenesis of many organs, but the mechanism and function in hepatocellular carcinoma (HCC) is still unclear. In the present study, we found that HSPA13 was highly expressed in HCC and predicted poor clinical prognosis. Upregulation of HSPA13 was significantly associated with vascular invasion in HCC patients. Functionally, knockdown experiments demonstrated that HSPA13 promoted HCC proliferation, migration, and invasion. Mechanistic investigation showed that HSPA13 could interact with TANK to inhibit its ubiquitination and degradation. In addition, the expression of HSPA13 and TANK were positively correlated in HCC tissues. To conclude, the present study uncovers the oncogenic function of HSPA13 in the progression of HCC by regulating the stability of TANK. These findings suggest that HSPA13 and TANK may serve as promising targets for the diagnosis and treatment of HCC., (© 2023. The Author(s).)

Background and Aims: Lenvatinib is a first-line drug commonly used in the treatment of advanced hepatocellular carcinoma (HCC). However, its clinical efficacy is very limited due to drug resistance. Therefore, there is a great need to explore its combination with other agents to achieve better therapeutic effects. Metformin has been demonstrated to show an anti-cancer effect. This study aimed to investigate the combined effect of lenvatinib with metformin in HCC cells both in vitro and in vivo and elucidate the possible molecular mechanisms., Methods: Flow cytometry, colony formation, CCK-8 and transwell assays were used to study the effect of Lenvatinib-Metformin combination on the malignant behaviour of HCC cells in vitro. Constructing an animal model of tumour-bearing to study the effect of combined drugs on HCC in vivo. Western blot experiments were performed to assess the relationship between AKT and FOXO3 and the cellular translocation of FOXO3., Results: Our results suggested that Lenvatinib and Metformin synergistically inhibited HCC growth and motility. Mechanistically, the combination of Lenvatinib and Metformin synergistically suppressed the activation of the AKT signalling pathway, which in turn reduced the phosphorylation level of downstream effector FOXO3 and induced its nuclear aggregation. In vivo studies further confirmed the synergistic suppression of lenvatinib with metformin in HCC growth., Conclusion: The Lenvatinib-Metformin combination may provide a potential therapeutic strategy to improve the prognosis of HCC patients., (© 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Helicase-like transcription factor (HLTF) belongs to the family of SWI/SNF proteins, which has been reported to exert oncogenic function in several human cancers. However, to date, its functional role in hepatocellular carcinoma (HCC) has not been revealed. Here, we found that HLTF was highly expressed in HCC tissues compared to nontumor tissues. Additionally, upregulation of HLTF was significantly associated with poor prognosis of patients with HCC. Functional experiments demonstrated that knockdown of HLTF expression significantly inhibited the proliferation, migration, and invasion of HCC cells in vitro, and suppressed tumor growth in vivo. In conclusion, our results suggest that upregulation of HLTF is associated with the development of HCC, and HLTF may be a potential therapeutic target for HCC treatment., (© 2023. The Author(s) under exclusive licence to Japan Human Cell Society.)

As the COVID-19 outbreak has an impact on the global economy, there will be interest in how China's financial markets function during the outbreak. To investigate the path of risk contagion in China's financial sub-markets before and after the COVID-19 outbreak, we divided the 2016-2021 period into two phases. Based on the time of the COVID-19 outbreak, we divided the new stage of economic development into pre-epidemic and post-epidemic stages and employed the DCC-GARCH model to investigate the dynamic correlation coefficients among the financial sub-markets in China. Furthermore, we employed complex network theory and the minimum tree model to describe the risk contagion path between two-stage Chinese financial submarkets. Finally, we provided pertinent recommendations for investors and policymakers and conducted a brief discussion based on the findings of the research.

RNF31 (HOIP), RBCK1 (HOIL-1L), and SHARPIN are subunits of the linear ubiquitin chain assembly complex. Their function and specific molecular mechanisms in hepatocellular carcinoma (HCC) have not been reported previously. Here, we investigated the role of RNF31 and RBCK1 in HCC. We showed that RNF31 and RBCK1 were overexpressed in HCC and that upregulation of RNF31 and RBCK1 indicated poor clinical outcomes in patients with HCC. RNF31 overexpression was significantly associated with more satellite foci and vascular invasion in patients with HCC. Additionally, RBCK1 expression correlated positively with RNF31 expression in HCC tissues. Functionally, RBCK1 and RNF31 promote the metastasis and growth of HCC cells. Moreover, the RNF31 inhibitor gliotoxin inhibited the malignant behavior of HCC cells. Mechanistically, RBCK1 interacted with RNF31 and repressed its ubiquitination and proteasomal degradation. In summary, the present study revealed an oncogenic role and regulatory relationship between RBCK1 and RNF31 in facilitating proliferation and metastasis in HCC, suggesting that they are potential prognostic markers and therapeutic targets for HCC., (© 2022. The Author(s).)

Cancer-associated fibroblasts (CAFs) are crucial components of the tumor microenvironment. Fibroblast activation protein (FAP) is overexpressed in CAFs. FAP-targeted molecular imaging agents, including the FAP inhibitors (FAPIs) 04 and 46, have shown promising results in tumor diagnosis. However, these molecules have a relatively short tumor-retention time for peptide-targeted radionuclide therapy applications. We aimed to design a 68 Ga-labeled FAPI dimer, 68 Ga-DOTA-2P(FAPI) 2 , to optimize the pharmacokinetics and evaluate whether this form is more effective than its monomeric analogs. Methods: 68 Ga-DOTA-2P(FAPI) 2 was synthesized on the basis of the quinoline-based FAPI variant (FAPI-46), and its binding properties were assayed in CAFs. Preclinical pharmacokinetics were determined in FAP-positive patient-derived xenografts using small-animal PET and biodistribution experiments. The effective dosimetry of 68 Ga-DOTA-2P(FAPI) 2 was evaluated in 3 healthy volunteers, and PET/CT imaging of 68 Ga-FAPI-46 and 68 Ga-DOTA-2P(FAPI) 2 was performed on 3 cancer patients. Results: 68 Ga-DOTA-2P(FAPI) 2 was stable in phosphate-buffered saline and fetal bovine serum for 4 h. The FAPI dimer showed high affinity and specificity for FAP in vitro and in vivo. The tumor uptake of 68 Ga-DOTA-2P(FAPI) 2 was approximately 2-fold stronger than that of 68 Ga-FAPI-46 in patient-derived xenografts, whereas healthy organs showed low tracer uptake and fast body clearance. The effective dose of 68 Ga-DOTA-2P(FAPI) 2 was 1.19E-02 mSv/MBq, calculated using OLINDA. Finally, the PET/CT scans of the 3 cancer patients revealed higher intratumoral uptake of 68 Ga-DOTA-2P(FAPI) 2 than of 68 Ga-FAPI-46 in all tumor lesions (SUV max , 8.1-39.0 vs. 1.7-24.0, respectively; P < 0.001). Conclusion: 68 Ga-DOTA-2P(FAPI) 2 has increased tumor uptake and retention properties compared with 68 Ga-FAPI-46, and it could be a promising tracer for both diagnostic imaging and targeted therapy of malignant tumors with positive expression of FAP., (© 2022 by the Society of Nuclear Medicine and Molecular Imaging.)

Long non-coding RNAs are essential to hepatocellular carcinoma (HCC) development, progression, and incidence of drug resistance. However, the biological significance of long non-coding RNA muskelin 1 antisense RNA (MKLN1-AS) remains poorly characterized. In this study, we observed noticeable increased levels of MKLN1-AS in HCC tissues. This upregulation of MKLN1-AS was clinically associated with vascular invasion and decreased disease-free survival and overall survival of patients with HCC. Functionally, MKLN1-AS-knockdown dramatically suppressed the metastasis and growth of HCC cells in vitro and in vivo . Additionally, the knockdown of MKLN1-AS augmented the pro-apoptosis effect of lenvatinib. Taken together, our findings indicate that MKLN1-AS may be exploited as a potential prognostic predictor and therapeutic target for HCC treatment.

Background: Emerging evidences have highlighted the roles of neutrophils, as the major host microenvironment component, in the development of hepatocellular carcinoma (HCC). Neutrophils extracellular traps (NETs) produced in the infection can strengthen the behavior of cancer metastasis. Here, we investigated the roles of NETs in HCC metastasis and further explore the underlying mechanism of how NETs interact with cancer., Methods: The neutrophils were isolated from whole blood of HCC patients and used to evaluate the formation of NETs. NET markers were detected in tissue samples, plasma and cell climbing slice. Mouse models were used to evaluate the roles of NETs in HCC metastasis in vivo, and the corresponding mechanisms were explored using in vivo and in vitro assays., Results: An increase in the release of NETs in patients with HCC, particularly those with portal vein tumor thrombosis (PVTT). The presence of NETs in HCC tumor tissues closely correlated with a poor prognosis. Functionally, the invasion ability of HCC cells was enhanced by co-culture with HCC neutrophils, through NETs formation, while the neutrophils from a healthy donor (HD) exhibited the inhibition of the invasion ability. Furthermore, we observed an enhanced ability of forming NETs in neutrophils from HCC patients in vitro, especially patients with PVTT or extra-hepatic metastasis. An in-vivo animal study demonstrated that neutrophils of HCC facilitated the metastatic behavior towards the lung. The further mechanistic investigation unveiled that HCC cells-derived cytokine IL-8 triggered NETs formation in an NADPH oxidase-dependent manner, and NETs-associated cathepsin G (cG) promoted HCC metastasis in vitro as well as vivo. Clinically, the expression of the cG protein in tumor tissues displayed a close correlation with the disease prognosis of HCC patients., Conclusion: Our findings implicated that the induction of NETs by HCC cells is a critical metastasis-supporting cancer-host interaction and that NETs may serve as an immune-based potential therapeutic target against HCC progression., Competing Interests: The authors reported no conflicts of interest for this work., (© 2021 Guan et al.)

Purpose: This study aimed to evaluate the potential utility of [ 68 Ga]Ga-FAPI-04 PET/CT for diagnosing primary and metastatic lesions in patients with liver cancer, as well as to compare it with contrast-enhanced CT (CE-CT), liver MRI, and [ 18 F]-FDG PET/CT., Methods: We performed a single-center post hoc retrospective analysis of data obtained from a prospective parent study (NCT04416165). This study included 34 patients diagnosed with or suspected hepatic lesions who underwent concomitant [ 68 Ga]Ga-FAPI-04 and [ 18 F]-FDG/CT scans. Moreover, these patients underwent liver MRI (n = 34) and CE-CT (n = 25). Histopathologic (n = 62) or radiographic follow-up (n = 128) served as the reference standard for the final diagnosis., Results: Among the 34 patients, 20, 12, and 2 patients presented with hepatocellular carcinomas, intrahepatic cholangiocarcinomas, and benign hepatic nodules, respectively. The sensitivities of CE-CT, MRI, [ 68 Ga]Ga-FAPI-04, and [ 18 F]-FDG/CT for detecting primary liver tumors were 96%, 100%, 96%, and 65%, respectively. Regarding the diagnosis of all intrahepatic lesions, the per-lesion detection rate of [ 68 Ga]Ga-FAPI-04 PET/CT was slightly lower than that of MRI (85% vs. 100%, P = 0.34) and significantly higher than that of [ 18 F]-FDG PET/CT (85% vs. 52%, P < 0.001). Regarding the diagnosis of all malignant lesions (including extrahepatic disease), the tumor detection rate of [ 68 Ga]Ga-FAPI-04 PET/CT was 87.4%, which was significantly higher than that of [ 18 F]-FDG PET/CT (65.0%, P < 0.001)., Conclusions: Our findings indicate that the sensitivity of [ 68 Ga]Ga-FAPI-04 PET/CT to correctly identify primary liver tumors and metastatic lesions is equivalent to that of CE-CT and liver MRI. Moreover, [ 68 Ga]Ga-FAPI-04 PET/CT is better at identifying liver lesions than [ 18 F]-FDG PET/CT, and its use may improve tumor staging, recurrence detection, and implementation of necessary treatment modifications.

Retinoid X receptor alpha (RXRα), a nuclear receptor of transcription factor, controls various physiological and pathological pathways including cellular growth, proliferation, differentiation, and apoptosis. Here, we report that RXRα is phosphorylated at its N-terminal A/B domain by cyclin-dependent kinase 1 (Cdk1) at the onset of mitosis, triggering its translocation to the centrosome, where phosphorylated-RXRα (p-RXRα) interacts with polo-like kinase 1 (PLK1) through its N-terminal A/B domain by a unique mechanism. The interaction promotes PLK1 activation, centrosome maturation, and mitotic progression. Levels of p-RXRα are abnormally elevated in cancer cell lines, during carcinogenesis in animals, and in clinical tumor tissues. An RXRα ligand XS060, which specifically inhibits p-RXRα/PLK1 interaction but not RXRα heterodimerization, promotes mitotic arrest and catastrophe in a tumor-specific manner. These findings unravel a transcription-independent action of RXRα at the centrosome during mitosis and identify p-RXRα as a tumor-specific vulnerability for developing mitotic drugs with improved therapeutic index., Competing Interests: Declaration of Interests The authors declare no competing interests., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Purpose: We evaluated the potential usefulness of [ 68 Ga]Ga-DOTA-FAPI-04 positron emission tomography/computed tomography (PET/CT) for the diagnosis of primary and metastatic lesions in various types of cancer, compared with [ 18 F] FDG PET/CT., Methods: A total of 75 patients with various types of cancer underwent contemporaneous [ 68 Ga]Ga-DOTA-FAPI-04 and [ 18 F] FDG PET/CT either for an initial assessment or for recurrence detection. Tumour uptake was quantified by the maximum standard uptake value (SUV max ). The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and accuracy of [ 18 F] FDG and [ 68 Ga]Ga-DOTA-FAPI-04 PET/CT were calculated and compared to evaluate the diagnostic efficacy., Results: The study cohort consisted of 75 patients (47 males and 28 females; median age, 61.5 years; age range, 32-85 years). Fifty-four patients with 12 different tumour entities underwent paired [ 68 Ga]Ga-DOTA-FAPI-04 and [ 18 F] FDG PET/CT for initial assessment, while the other 21 patients underwent paired scans for recurrence detection. [ 68 Ga]Ga-DOTA-FAPI-04 PET/CT was able to clearly identify 12 types of malignant tumours with favourable tumour-to-background contrast, which resulted in a higher detection rate of primary tumours than did [ 18 F] FDG PET/CT (98.2% vs. 82.1%, P = 0.021). Meanwhile, [ 68 Ga]Ga-DOTA-FAPI-04 PET/CT showed a better sensitivity than [ 18 F] FDG PET/CT in the detection of lymph nodes (86.4% vs. 45.5%, P = 0.004) and bone and visceral metastases (83.8% vs. 59.5%, P = 0.004)., Conclusion: [ 68 Ga]Ga-DOTA-FAPI-04 PET/CT showed a superior diagnostic efficacy than [ 18 F] FDG PET/CT for the diagnosis of primary and metastatic lesions in patients with various types of cancer, especially in identifying liver metastases, peritoneal carcinomatosis, and brain tumours.

Growing evidence indicates that deubiquitinase ubiquitin-specific protease 11 (USP11) plays an important role in cellular function by regulating the stability of its substrates. USP11 is dysregulated in many types of cancer and involved in tumor development and progression. We previously showed that USP11 was upregulated in hepatocellular carcinoma (HCC) and promoted HCC cell invasion and metastasis potency. However, the mechanism underlying the role of USP11 in HCC cell metastasis and its function in cell proliferation remain unknown. Here, CCK-8, soft agar assays and nude mouse models showed that USP11 was essential for HCC cells survival and proliferation in vitro and in vivo . Results form mass spectrometry, co-immunoprecipitation, and ubiquitination assays demonstrated that USP11 interacted with nuclear factor 90 (NF90) and promoted its deubiquitination, thereby stabilizing it in HCC cells. Moreover, the effect of USP11 on promoting HCC cells proliferation and metastasis was dependent on NF90, and USP11 expression was positively correlated with NF90 expression in human HCC tissues, as demonstrated via immunohistochemistry. Collectively, the present findings indicated that USP11 binded to and deubiquitinated NF90, thereby stabilizing the protein expression level and promoting HCC cell proliferation and metastasis. NF90 was identified as an important downstream target of USP11. Dysregulated signaling of this novel USP11/NF90 axis might promote HCC proliferation and metastasis, and the axis could be a potential therapeutic target in HCC., Competing Interests: None., (AJCR Copyright © 2020.)

Hepatocellular carcinoma (HCC) has emerged as one of the most common malignancies worldwide. It is associated with a high mortality rate, as evident from its increasing incidence and extremely poor prognosis. The deubiquitinating enzyme 26S proteasome non-ATPase regulatory subunit 14 (PSMD14) has been reported to act as an oncogene in several human cancers. The present study aimed to reveal the functional significance of PSMD14 in HCC progression and the underlying mechanisms. We found that PSMD14 was significantly upregulated in HCC tissues. Overexpression of PSMD14 correlated with vascular invasion, tumor number, tumor recurrence, and poor tumor-free and overall survival of patients with HCC. Knockdown and overexpression experiments demonstrated that PSMD14 promoted proliferation, migration, and invasion in HCC cells in vitro, and facilitated tumor growth and metastasis in vivo. Mechanistically, we identified PSMD14 as a novel post-translational regulator of GRB2. PSMD14 inhibits degradation of GRB2 via deubiquitinating this oncoprotein in HCC cells. Furthermore, pharmacological inhibition of PSMD14 with O-phenanthroline (OPA) suppressed the malignant behavior of HCC cells in vitro and in vivo. In conclusion, our findings suggest that PSMD14 could serve as a novel promising therapeutic candidate for HCC., (Copyright © 2019 Elsevier B.V. All rights reserved.)

The cross-talk between hepatic stellate cells (HSCs) and hepatic carcinoma cells contributes to hepatocellular carcinoma (HCC) progression, but the underlying mechanism is largely unknown. We report here that activated HSCs induce upregulation of nicotinamide N-methyltransferase (NNMT), which is known to regulate multiple metabolic pathways in hepatoma cells of the liver. High levels of NNMT in HCC tissues were positively correlated with vascular invasion, increased serum HBV-DNA levels, and distant metastasis. In addition, functional assays showed that NNMT promoted HCC cell invasion and metastasis by altering the histone H3 methylation on 27 methylation pattern and transcriptionally activating cluster of differentiation 44 (CD44). NNMT-mediated N6-methyladenosine modification of CD44 mRNA resulted in the formation of a CD44v3 splice variant, while its product 1-methyl-nicotinamide stabilized CD44 protein by preventing ubiquitin-mediated degradation. Finally, NNMT was also shown to be a target of statins that inhibited metastasis of hepatoma cells. Taken together, our study shows for the first time that the NNMT/CD44v3 axis regulates HCC metastasis and presents NNMT as a promising prognostic biomarker and therapeutic target for HCC., (© 2019 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.)

Background: CDK5, an atypical member of the CDK family, play a significant role in the tumorigenesis of multiple organ, but CDK5 and its substrates in genesis and development of HCC is still unclear., Methods: Expression of CDK5 in HCC tumor and paired adjacent noncancerous tissues from 90 patients were measured by Western blotting, immunohistochemistry, and real-time PCR. The role of CDK5 in cell function and tumorigenesis was explored in HCC cell lines, ex vivo xenografts and diethylnitrosamine induced HCC model. Furthermore, comparative phosphoproteomic screening identified the oncoprotein TPX2 as a new substrate of CDK5. We also identified the effect of CDK5/P25 interaction blocker tamoxifen on HCC cell growth and migration., Results: CDK5 was increased in HCC tisues and the level of CDK5 was correlated with the severity of HCC based on patient recurrence and 5-year fatality rate. Exogenously expressed CDK5 but not kinase-dead CDK5 promoted proliferation, migration, and invasion of HCC cells. Functional ablation of CDK5 significantly inhibited the exacerbation of HCC cells. Xenograft implantation of HCC cells overexpressing CDK5 promoted tumorigenesis, and genetic knockdown of CDK5 reduced HCC growth and metastasis in vivo. More importantly, heterozygous knockout CDK5 (Cdk5+/-) attenuated HCC tumorigenesis induced by diethylnitrosamine. CDK5-mediated phosphorylation of TPX2 at serine 486 promoted its protein stability. TPX2 silence could restore HCC cell migration capability with overexpression CDK5. Treatment with tamoxifen inhibited cell growth and migration of HCC, demonstrating the role of active CDK5 in HCC., Conclusions: Our results suggest activation of CDK5 is associated with HCC tumorigenesis. CDK5-mediated phosphorylation and stabilization of TPX2 promotes hepatocellular proliferation and tumorigenicity.

Hepatocellular carcinoma (HCC) is correlated with a poor prognosis and high mortality worldwide. Neuronal pentraxin 1 (NPTX1) has been reported to play an oncogenic role in several types of tumors. However, its expression and function in HCC is not yet fully understood. In the present study, we aimed to investigate the clinicopathological significance of NPTX1 in HCC and the underlying mechanisms. We observed that the expression of NPTX1 was decreased significantly in HCC and was associated with tumor size and metastasis in patients. Gain-of-function approaches revealed that NPTX1 suppressed the growth ability of HCC cells and contributed to mitochondria- related apoptosis. Furthermore, mechanistic investigations showed that the AKT (AKT serine/threonine kinase) pathway can regulate the effects of NPTX1 in HCC cells. After blocking the AKT pathway, the action of NPTX1 was greatly increased. In summary, we demonstrated that NPTX1 inhibited growth and promoted apoptosis in HCC via an AKT-mediated signaling mechanism. These findings indicate that NPTX1 is a potential clinical therapeutic target., (© 2019 The Author(s).)

Background: Due to the high recurrence and metastasis rate, the clinical outcomes of patients with hepatocellular carcinoma (HCC) are still unsatisfactory. Hepatitis B virus X-interacting protein (HBXIP) has been reported to play crucial roles in carcinogenesis. Purpose: We aimed to reveal the functional significance and underlying mechanism of HBXIP in HCC metastasis. Methods: Cell transwell assay, in vivo metastasis model, real-time PCR, western blot analysis, luciferase reporter and chromatin immunoprecipitation assays were applied. Results: Here, we detected the HBXIP expression level and determined its clinical significance in HCC. We found that HBXIP was significantly upregulated in HCC tissues, and correlated with vascular invasion, tumor metastasis and worse prognosis of HCC patients. HBXIP enhanced cell migration and invasion in vitro, and promoted the metastasis of HCC in vivo. Furthermore, we confirmed that HBXIP increased MMP15 expression through association with proto-oncogene c-myc. Depletion of c-myc abolished HBXIP-mediated MMP-15 upregulation. We also observed a positive correlation between HBXIP and MMP15 expression in HCC tissues. Conclusion: Our results establish a novel function for HBXIP-MMP15 regulation in HCC metastasis and suggest its candidacy as a new prognostic biomarker and therapeutic target for HCC metastasis., Competing Interests: The authors report no conflicts of interest in this work.

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related mortality worldwide. Recently, ubiquitin-conjugating enzyme E2C (UBE2C) has been reported to be overexpressed in human cancers and act as a potential oncogene. However, little is known about the functional roles of UBE2C in HCC progression. In the present study, analysis of UBE2C mRNA expression in The Cancer Genome Atlas (TCGA) dataset reveals that significantly higher UBE2C mRNA levels was found in HCC tissues and associated with higher HCC grade. Elevated UBE2C mRNA levels in HCC indicated worsened survival probabilities. Through performing loss-of-function assays, we demonstrated that knockdown of UBE2C expression obviously suppressed proliferation, migration, and invasion of HCC cells in vitro Moreover, HCC cells with UBE2C knockdown showed higher sensitivity for the treatment of chemotherapeutic drug, including adriamycin (ADR) and 5-fluorouracil (5-FU). Silencing of UBE2C also increased the sensitivity of HCC cells to sorafenib, an approved treatment for patients with advanced-stage HCC. Our findings strongly suggest that UBE2C emerges as a marker for prognosis in HCC, and blocking UBE2C may be a novel strategy for HCC therapies., (© 2019 The Author(s).)

Background: Hepatocellular carcinoma (HCC) is one of the most frequent cancers and the third leading cause of cancer-related deaths. It has been reported that lysosomal associated transmembrane protein LAPTM4B expression is significantly upregulated in human cancers and closely associated with tumor initiation and progression. Purpose: We aimed to reveal the relevance of LAPTM4B and the pathogenesis of HCC. Methods: Cell viability assessment, colony formation assay, in vivo xenograrft model, microarray, real-time PCR, immunofluorescence and western blot analysis were applied. Results: Our results demonstrated that LAPTM4B promoted HCC cell proliferation in vitro and tumorigenesis in vivo . Additionally, upon starvation conditions, LAPTM4B facilitated cell survival, inhibited apoptosis and induced autophagic flux. Expression profiling coupled with gene ontology (GO) analysis revealed that 159 gene downregulated by LAPTM4B silencing was significantly enriched in response to nutrient and some metabolic processes. Moreover, LAPTM4B activated ATG3 transcription to modulate HCC cell apoptosis and autophagy. Conclusion:  Our findings demonstrate that LAPTM4B acts as an oncogene that promotes HCC tumorigenesis and autophagy, and indicate that LAPTM4B may be used as a novel therapeutic target for HCC treatment., Competing Interests: The authors report no conflicts of interest in this work.

DHX15 is an outstanding member of the DEAH-box RNA helicase family. A few studies suggest that DHX15 contributes to carcinogenesis in several tumor cell lines. However, whether DHX15 acts as an oncogene or tumor suppressor and its association with hepatocellular carcinoma (HCC) prognosis are still poorly understood. To address this question, we used immunohistochemistry to evaluate DHX15 expression patterns and their association with clinicopathological factors and the prognosis of patients with HCC. Our results showed that DHX15 expression was significantly higher in cancerous tissues than that in nontumor tissues (P < .0001). DHX15 expression in HCC patients was associated with differentiation status (P = .018), tumor number (P = .048), intrahepatic or extrahepatic metastasis (P = .001), serum α-fetoprotein (P = .006), hepatitis B virus level (P = .018), and recurrence (P < .001). In addition, the survival analysis revealed that the DHX15-high group had significantly decreased overall survival time (P = .004) and lower 1-year survival rates (P = .002) compared with the DHX15-low group. Furthermore, multivariate analysis identified DHX15 expression as an independent factor associated with poor prognosis in HCC (P = .036). In summary, these findings demonstrate, for the first time, that DHX15 is significantly upregulated in HCC and its high expression was correlated with poor prognosis, suggesting its pivotal role in the progression of HCC. The present results suggest that DHX15 may serve as a potential prognostic biomarker for HCC patients., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Purpose: The purpose of this study was to evaluate the differential diagnostic value of 2-[fluorine-18]-fluoro-2-deoxy-d-glucose ( 18 F-FDG) positron emission tomography (PET)/computed tomography (CT) for benign and malignant vertebral compression fractures (VCFs), where the diagnostic accuracy of 18 F-FDG PET/CT was compared with magnetic resonance imaging (MRI)., Patients and Methods: Between 2015 and 2017, we retrospectively evaluated 87 patients with 116 VCFs. MRI was performed in all the 87 patients, whereas 18 F-FDG PET/CT was executed in 51 patients. Three malignant features (convex posterior cortex, epidural mass formation, and pedicle enhancement) from MRI and the maximum standardized uptake value (SUV max ) from 18 F-FDG PET/CT were evaluated in benign and malignant VCFs, respectively. Sensitivity, specificity, positive predictive value, and negative predictive value of MRI and 18 F-FDG PET/CT were compared in the differentiation of malignant from benign VCFs., Results: The results of our investigation showed that the sensitivity and specificity for predicting malignant VCFs were 75.6% and 77.3% for convex posterior cortex, 82.9% and 813% for epidural mass formation, and 85.7% and 70.8% for pedicle enhancement. 18 F-FDG PET/CT demonstrated higher sensitivity (100%) but lower specificity (38.9%) as compared to MRI with regard to differentiation between benign and malignant VCFs. A significant difference in the SUV max values was observed between the benign and malignant fractures (2.9 ± 1.0 vs 5.0 ± 1.8, P < 0.01). Besides the value of SUV max , it has been noticed that the FDG uptake pattern differed in malignant and benign fractures., Conclusion: Significant MRI findings such as convex posterior cortex, epidural mass formation, and pedicle enhancement are highly suggestive of malignancy. 18 F-FDG PET/CT reliably differentiated the fractures of malignant from benign based on both SUV max and 18 F-FDG uptake pattern. In a situation where MRI findings are not diagnostic, 18 F-FDG PET/CT provides additional information as it has high sensitivity and is semiquantitative., Competing Interests: Disclosure The authors report no conflicts of interest in this work.

Hepatocellular carcinoma (HCC) is associated with high metastatic potential and high mortality. Accumulating evidence has demonstrated that speckle-type POZ protein (SPOP) is a key adaptor molecule of ubiquitination. However, the molecular mechanism of SPOP-mediated ubiquitination in HCC metastasis remains obscure. In the present study, our results indicated that SPOP expression was significantly downregulated in HCC and was associated with tumor size, differentiation and metastasis. Cox regression model showed that low SPOP expression was a risk factor related to the prognosis of HCC patients. Loss- and gain-of-function assays demonstrated that SPOP inhibited HCC cell migration and invasion in vitro. Mechanisitically, co-immunoprecipitation and ubiquitination assays revealed that SPOP recognized and bound SENP7 and promoted its degradation via ubiquitin-dependent proteolysis. Analysis of immunohistochemistry showed that vimentin expression was correlated negatively with SPOP and positively with SENP7. These results implied that increased degradation of SENP7 by overexpression of SPOP decreased vimentin levels, which in turn attenuated HCC cell metastasis. Moreover, in vivo assays showed that SPOP overexpression also significantly suppressed liver and lung metastases. In summary, SPOP inhibits HCC cell metastasis via ubiquitin-dependent SENP7 proteolysis and may thus serve as a new opinion for the prevention of HCC metastasis., (Copyright © 2018. Published by Elsevier Inc.)

Ubiquitin-specific protease 11 (USP11) is a deubiquitinating enzyme that exerts its biological functions by regulating multiple signaling pathways such as p53, NF-κB, TGF-β, and Hippo. A large body of evidence supports a link between UPS11 and tumorigenesis. However, the clinical significance and biological function of USP11 in hepatocellular carcinoma (HCC) remains unclear. Here, USP11 expression was assessed by immunohistochemistry in a pilot series of 71 HCC clinical samples, and the association between USP11 expression and clinicopathological features and overall survival time was analyzed. The cytoplasmic expression rate of USP11 was higher in non-cancerous tissue than that in cancer tissue (36.6 vs. 12.7%, P = 0.001), whereas the nuclear expression rate of USP11 was lower in non-cancerous tissue (5.6 vs. 69.0%, P < 0.001). USP11 expression level was higher in tumor than that in non-tumor tissue (P < 0.001). Chi-square analysis of variances suggested that USP11 expression was associated with vascular invasion (P = 0.033), differentiation (P = 0.027), tumor number (P = 0.009), and recurrence (P = 0.036). USP11 expression was also associated with shorter overall survival time (P = 0.001) by log-rank test. Unconditional logistic regression analysis with multiple covariates indicated that high USP11 expression was associated with a 2.96-fold increase in the risk of death compared with low USP11 levels (P = 0.041) and acted as an independent predictor of overall survival. HCC patients with simultaneously high USP11 and alpha-fetoprotein expression had an adjusted 5-fold higher risk of all-cause-related death (P = 0.006). Moreover, in vitro and in vivo experiments confirmed that USP11 could promote the migration and invasion of HCC cell. Overall, we suggest that USP11 promotes HCC cell metastasis, and we provide the first evidence of the prognostic significance of USP11 expression in HCC, which suggests that USP11 is a promising therapeutic target for the treatment of HCC.

Hepatocellular carcinoma (HCC) accounts for a large proportion of cancer-associated mortality worldwide. The functional impact of long noncoding RNAs (lncRNAs) in human cancer is not fully understood. Here, we identified a novel oncogenic lncRNA termed as lncPARP1 , which was significantly up-regulated in HCC. Increase in lncPARP1 expression was associated with age, α-fetoprotein (AFP) levels, tumor size, recurrence, and poor prognosis of HCC patients. Loss-of-function approaches showed that knockdown of lncPARP1 inhibited proliferation, migration, and invasion, while induced apoptosis in HCC cells. Moreover, mechanistic investigation demonstrated that PARP1 was an underlying target of lncPARP1 in HCC. In summary, we provide the first evidence that lncPARP1 exerts an oncogene to promote HCC development and progression, at least in part, by affecting poly (ADP-ribose) (PAR) polymerase 1 (PARP1) expression., (© 2018 The Author(s).)

Postoperative recurrence and metastasis are the major problems for the current treatment of hepatocellular carcinomas (HCC) in the clinic, including hepatectomy and liver transplantation. Here, we report that arsentic-loaded nanoparticles (ALNPs) are able to reduce the invasion of HCC cells in vitro, and, more importantly, can strongly suppress the invasion and metastasis of HCC in vivo without adverse side effects. Compared to free drug arsenic trioxide , ALNPs can deliver the drug into cancer cells more efficiently, destroy the structure of microtubules and reduce the aggregation of microfilaments in cell membranes more significantly. Furthermore, our results also reveal that tumor cells in murine blood were reduced remarkably after intravenous injection of ALNPs, indicating that this nano-drug may efficiently kill circulating tumor cells in vivo. In conclusion, our nano-drug ALNPs have great potential for the suppression of metastasis of HCC, which may open up a new avenue for the effective treatment of HCC without metastasis and recurrence.

Recently, many studies show that long non-coding RNAs (lncRNAs) play important roles in cancer biology. Although its expression was reported dysregulated during tumorigenesis, the contributions of lncRNAs to hepatocellular carcinoma (HCC) are still largely unknown. In particular, the lncRNA CARLo-5 has a functional role in cell-cycle regulation in colon cancer, while the clinical significance and biological function of CARLo-5 in HCC remain unelucidated. In order to fill those study blanks, the expression level of CARLo-5 in human HCC specimens was tested, and its correlation with clinicopathologic features as well as the prognosis for patients with HCC was analyzed. Additionally, MTT, wound healing and transwell assays were employed to investigate the biological function of CARLo-5. The results showed that CARLo-5 levels were significantly overexpressed in HCC tissues compared to ANLT. Besides, high expression of CARLo-5 was associated with liver cirrhosis (P = 0.001), tumor number (P < 0.001), vascular invasion (P = 0.001), capsular formation (P = 0.014) and Edmondson-Steiner grade (P < 0.001), which proved that CARLo-5 was an independent risk factor for overall survival and disease-free survival. In addition, in highly metastatic HCC cell lines (HCCLM3 and MHCC97-L), CARLo-5 was up-regulated, but in lowly metastatic HCC cell lines (HepG2, SNU387), it showed down-regulated. Besides, by using gain and loss of function experiments in HCC cell lines (HCCLM3 and HepG2), the results showed that CARLo-5 overexpression significantly enhanced cell proliferation, migration and invasion in vitro. Our study also revealed that CARLo-5 was prominently up-regulated in HCC specimens and its high expression was associated with poor prognosis of HCC patients. Totally, those findings together indicate that CARLo-5 promotes proliferation and metastasis of HCC and potentially emerged as a novel therapeutic target.

Pygopus-2 over-expression has been reported in several malignancies, such as ovarian, breast, lung and liver cancers. Here we demonstrated that down-regulation of Pygopus-2 by shRNA inhibited hepatic carcinoma cell invasion in vitro and metastasis in xenograft tumor models, which were promoted when Pygopus-2 was over-expressed. Pygopus-2 increased hepatic carcinoma cell invasion and metastasis, by decreasing E-cadherin. Pygopus-2 could bind to the E-cadherin promoter, increasing its methylation, and also indirectly decreased zeb2 expression. In turn these effects caused down-regulation of E-cadherin, potentiating invasion and metastasis. We suggest that targeting Pygopus-2 may potentially inhibit metastasis of hepatic carcinoma.